Alzheimer's disease (AD) is the most common form of both senile and presenile dementia in the world and is recognized clinically as relentlessly progressive dementia that presents with increasing loss of memory, intellectual function and disturbances in speech (Merritt, 1979, A Textbook of Neurology, 6th edition, 484–489 Lea & Febiger, Philadelphia). The disease itself usually has a slow and insidious progress that affects both sexes equally, worldwide. It begins with mildly inappropriate behavior, uncritical statements, irritability, a tendency towards grandiosity, euphoria and deteriorating performance at work; it progresses through deterioration in operational judgement, loss of insight, depression and loss of recent memory; it ends in severe disorientation and confusion, apraxia of gait, generalized rigidity and incontinence (Gilroy and Meyer, 1979, Medical Neurology, 175–179 MacMillan Publishing Co.). Alzheimer's disease afflicts an estimated 4 million human beings in the United States alone at a cost of 35 billion dollars a year (Hay and Ernst, Am. J. Public Health, 77:1169–1175 (1987)). It is found in 10% of the population over the age of 65 and 47% of the population over the age of 85 (Evans, et al., JAMA, 262:2551–2556 (1989)). In addition, the disease is found at much lower levels in the younger age groups, usually beginning at about 30 years of age and even rarely in late childhood (Adams and Victor, Principles of Neurology, 401–407 (1977)).
Proteases and, in particular, aspartyl proteases have been implicated in diseases, such as Alzheimer's Disease, that are characterized by the accumulation of amyloid plaques. Amyloidogenic Aβ peptides (Aβ) are the principle component of the amyloid plaques that accumulate intracellularly and extracellularly in the neuritic plaques in the brain in AD. Aβ is a 4.5 kD protein, about 40–42 amino acids long, that is derived from the C-terminus of amyloid precursor protein (APP). APP is a membrane-spanning glycoprotein that, in the normal processing pathway, is cleaved inside the Aβ protein to produce α-sAPP, a secreted form of APP. Formation of alpha α-sAPP precludes formation of Aβ. It has been proposed that Aβ accumulates by virtue of abnormal processing of APP, so that compounds that inhibit the activity of the enzymes responsible for Aβ production are desirable (see, e.g., Wagner, et al., Biotech. Report, 106–107 (1994/1995); and Selkoe, TINS, 16:403–409 (1993)).
In addition to the accumulation of amyloid plaques, neurons in AD brains exhibit specific alterations in τ, a family of phosphoproteins that bind tubulin (Weingarten, et al., Proc. Natl. Acad. Sci. USA, 72:1858–1862 (1975); and Williams and Detrich, Biochemistry, 18:2499–2503 (1979)), and stabilize microtubules (Goode and Feinstein, J. Cell Biol., 124:769–782 (1994)). In these brains, τ proteins adopt an altered form and comprise the dominant component of abnormal cytosketal fibers known as paired helical filaments (PHFs) (see, Kosik, et al., Proc. Natl. Acad. Sci. USA, 83:4044–4088 (1986); Lee, et al., Science, 251:675–678 (1991); and Mann, et al., Neuropathol. Appl. Neurobiol., 13:123–139 (1987)). Molecular dissection of PHFs has revealed two specific alterations in τ. First, PHF-τ proteins maintain an excessively phosphorylated state throughout postmortem intervals (Matsuo, et al., Neuron, 13:989–1002 (1994)). Second, after treatment of PHFs with reducing agents and detergents, the remaining filaments contain truncated forms of τ (Nieto, et al., Biochem. Biophys. Res. Commun., 154:660–667 (1988); Nieto, et al., J. Neurosci., 37:163–170 (1990); and Wischik, et al., Proc. Natl. Acad. Sci. USA, 85:4506–4510 (1988)). These results suggest that modifications in the posttranslational processing of τ contribute to the formation of PHFs. It has been proposed that τ-fragments accumulate by virture of abnormal processing of τ by proteases (see, Bednarski and Lynch, J. Neurochem., 67(5):1845–1855 (1996)). As such, compounds that inhibit the acitivity of the enzymes responsible for τ-fragment production are desirable.
Because proteases are implicated in Alzheimer's Disease and in numerous other disorders, there remains a need in the art for the development of potent and specific inhibitors of these enzymes. Quite surprisingly, the present invention fulfills this and other need.